A platinum butterfly effect: small changes turn an anticancer drug into a non-toxic metalloantibiotic with in vivo efficacy

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Abstract Metal-based compounds have emerged as a promising class of potential antibiotics exhibiting high hit-rates against critical bacterial pathogens while not displaying higher toxicity than organic compounds. Here, we describe the exploration of novel, non-toxic, Gram-positive acting platinum-based antibacterial agents with high activity. Structure-activity relationship (SAR) studies revealed that the simplest scaffold showed the best antibacterial properties. Mode of action studies showed that lead compound Pt1 akin to the structurally similar chemotherapeutic cisplatin, causes reduced DNA staining, visible nucleoid compaction, and activation of DNA damage repair responses. Importantly, we show that Pt1 interacts with and damages DNA directly, resulting in DNA strand breaks and fragmentation. Pt1 activity can be reduced by hydroxyl radical scavengers, suggesting that Pt1 possesses a multimodal mechanism. In line with this observation, no resistance development to Pt1 was observed. Finally, we demonstrate the in vivo activity of Pt1 , which significantly reduced the bacterial load in a murine S. aureus skin infection model. These findings shed light on the SAR and antibacterial mode of action of a novel class of platinum metalloantibiotics, validate their in vivo efficacy, and pave the way for further exploration of platinum compounds as novel antibiotic drug candidates.

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